Cancer cells are more dangerous when they are on the move. Leong et al. (page 2935) now reveal that the Notch receptor sets cancer cells on this metastatic journey.

Breast cancer cells grow aggressively and enter the circulation when they stop expressing E-cadherin, which glues cells together. E-cadherin is suppressed by Notch signaling in some cell types during periods of development, when cells need to move around to form three-dimensional organs.

Increased levels of Notch and its ligand Jagged are found in breast cancer patients who have malignant tumors and are therefore less likely to survive. Leong et al. now find that Notch activation by Jagged frees cancer cells by shutting off their E-cadherin glue.

When Notch receptor levels were increased in E-cadherin–expressing human breast cancer cells, the cells turned on Slug—one of the several known transcriptional suppressors of E-cadherin. Slug levels were also increased in primary human breast cancers that had high levels of Jagged and Notch, suggesting that this Jagged–Notch–Slug pathway puts cancer cells on the road.

How Notch receptors are ramped up in cancer cells is unknown. But the availability of patients' cell lines that overexpress Notch receptors and ligands allowed the authors to transplant mice with human breast tumors. Mice transplanted with cancer cells that lacked E-cadherin developed metastatic tumors. The tumor growth and metastasis was prevented when E-cadherin expression was enforced by blocking Notch signaling with soluble Notch receptors. Whether these Notch inhibitors also block metastasis of human cancers remains to be tested.

Notch-mediated loss of E-cadherin also protected the cancer cells from apoptosis, which is normally triggered in cells that detach from their support structures. Metastasizing tumor cells that expressed Notch lacked caspase activity and thus survived the transit to new tumor sites. The team is now trying to understand how Notch blocks tumor cell apoptosis.